Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma).

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.

Treatment of chronic hepatitis D with interferon alfa-2a.

BACKGROUND AND METHODS: Chronic hepatitis D is a severe and rapidly progressive liver disease for which no therapy has been proved effective. To evaluate the efficacy of treatment with interferon, we studied 42 patients with chronic hepatitis D who were randomly assigned to receive either 9 million or 3 million units of recombinant interferon alfa-2a (three times a week for 48 weeks) or no treatment. RESULTS: By the end of the treatment period, serum alanine aminotransferase values had become normal in 10 of 14 patients receiving 9 million units (71 percent), as compared with 4 of 14 treated with 3 million units (29 percent, P = 0.029) and 1 of 13 untreated controls (8 percent, P = 0.001). Seven patients treated with the higher dose of interferon (50 percent) had a complete response (normal levels of alanine aminotransferase and no detectable serum hepatitis delta virus [HDV] RNA), as compared with three of those who received the lower dose (21 percent, P = 0.118), and none of the controls (P = 0.004). Treatment with 9 million units of interferon was associated with a marked improvement in the histologic findings (reduced periportal necrosis and portal and lobular inflammation), whereas in the untreated controls there was considerable histologic deterioration. In 5 of the 10 patients treated with 9 million units of interferon whose alanine aminotransferase values became normal, the biochemical responses persisted for up to 4 years (mean, 39 months), but the effects of treatment on viral replication were not sustained. In contrast, none of those who received 3 million units and none of the untreated controls had a sustained biochemical or virologic response. CONCLUSIONS: In about half the patients with chronic hepatitis D treated with high doses of interferon alfa-2a (9 million units three times a week for 48 weeks), the serum alanine aminotransferase level becomes normal, HDV RNA becomes undetectable in serum, and there is histologic improvement. However, a relapse is common after treatment has been stopped.

Cutaneous adverse reactions following the administration of nonsteroidal antiinflammatory drugs and antibiotics: an Italian survey.

The Italian Group for Epidemiological Research in Dermatology (GISED) collected a series of cutaneous adverse reactions following NSAID and/or antibiotics administered by topical and/or systemic route. Dermatologists from North and Central Italy took part in this survey by filling in 1457 case report forms during a four-month observation time in 1988-89. The main purpose of our epidemiological study aimed at evaluating a post-marketing surveillance program by examining spontaneous reports of cutaneous adverse reactions. This result seems to be noteworthy, considering the difficulties encountered in Italy to develop such a program.

Interferon alfa 2a in superficial bladder cancer prophylaxis: toleration and long-term follow-up. A phase I-II study.

Twenty patients (17 M., 3F., -mean age 61.5 yrs) affected by superficial bladder tumors (TINOMO) were included in the study. All patients had cold mucosa biopsy to exclude the presence of dysplasia or CIS; the histopathological grade was G1 in 19 cases and G2 in 1. The treatment was started between 3 to 7 days after radical TUR with intravesical instillations of recombinant Interferon alfa 2a, at the daily dose of 54 million/Units for 5 days for 2 consecutive weeks. No systemic adverse effects were observed. Local toleration and efficacy were assessed by cystoscopy, performed at the end of treatment after 6 weeks and then at three month intervals. At the first control 15% of patients showed an early local reaction with bollous oedema surrounding the resected area (with spontaneously disappeared after few days). No other abnormal findings were observed at the 6-week control. After a median follow-up of 98 weeks, 15 of the 19 evaluable patients (79%, C.I. 60-91) were disease-free. The median relapse time was 39.9 weeks, while clinical and local tolerance were optimal. These preliminary data confirm the complete absence of toxicity of Interferon alfa 2a administered at relatively high doses intravesically and indicate that this compound has some effect on superficial bladder cancer.

Neuroendocrine effects of interferon alpha 2-a in healthy human subjects.

The acute effects of interferon alpha-2a (3 x 10 IU im) on catecholamine and immunoreactive beta endorphin plasma levels, cortisol serum levels and lymphocyte beta 2-adrenoceptor density were evaluated in ten healthy volunteers. Interferon induced a significant increase in plasma norepinephrine; there was an increased norepinephrine standing response, too. On the contrary, epinephrine standing response was reduced by interferon. Lymphocyte beta 2-adrenoceptors decreased significantly after interferon administration; dissociation constant of binding was unchanged. Cortisol serum levels increased significantly with respect to control test, whereas immunoreactive beta endorphin did not change. These results support the hypothesis of functional relationships between neuroendocrine and immune systems; moreover they may be useful in clinical trials given the administration of interferon alpha in an increasing number of diseases.

Problems in the management of chronic hepatitis B with interferon: experience in a randomized, multicentre study.

In a multicentre trial, 82 patients known to be hepatitis B e antigen and hepatitis B virus DNA positive for at least 1 year, with elevated serum alanine aminotransferase levels and chronic liver lesions on biopsy, were randomized to receive either recombinant interferon alfa-2a at a dose of 4.5 million units thrice weekly for 4 months or no treatment. At the end of therapy, viral DNA clearance and aminotransferase normalization were significantly (p less than 0.05) more frequent in treated patients than in controls. After 16 months' follow up, the difference was still significant for hepatitis B e antigen clearance and transaminase normalization. Hepatitis B virus DNA reactivation was observed during follow up in 43% of treated patients and 50% of controls. Improvements in liver inflammation were observed in patients on interferon. High pre-treatment serum aminotransferase levels, female sex and a low score for fibrosis in the initial biopsy were predictive factors significantly (p less than 0.05) associated with termination of hepatitis B virus replication in treated cases. These results indicate that interferon is effective in inducing clearance of HBV from serum and improvement of biochemical and histological parameters of liver disease. However, a more prolonged regimen of therapy may be required to obtain stable suppression of hepatitis B virus replication.

Ceftriaxone plus amikacin in a single daily dose as empiric antibiotic therapy in granulocytopenic patients.

In our study ceftriaxone plus amikacin were employed as empirical antibiotic therapy. This antibiotic treatment allows for a once daily administration and has a broad spectrum of activity. 21 febrile episodes were treated with an antibiotic regimen of ceftriaxone 50 mg/kg/day and amikacin 30-35 mg/kg/day i.v. An earlier pilot study was carried out in which 47 febrile episodes were treated with an antibiotic regimen of ceftriaxone 80-100 mg/kg/day i.v. and amikacin 30-35 mg/kg/day i.v. in a single dose. The overall response rate was 76% (16/21) and 79% (37/47) for the pilot study. During the treatment no side effects were observed and aminoglycoside related toxicity did not occur. In conclusion, this empiric antibiotic therapy gives a high response rate and allows for a single daily administration.

Long-term effect of low dose recombinant interferon therapy in patients with chronic hepatitis B.

Thirty three heterosexual chronic hepatitis B virus (HBV) carriers were randomized, with stratification for disease activity, to receive intramuscular recombinant interferon alpha-2a (r-IFN) at doses of 4.5 megaunits thrice weekly for 4 months, or no treatment. During r-IFN treatment, serum HBV-DNA levels fell in all, but 2 patients. Final evaluation at 16 months after randomization revealed that the rate of complete response, i.e., loss of both HBV-DNA and HBeAg with ALT normalization was 22.2% (2 of 9 cases) in patients on interferon and 12.5% (1 of 8 cases) in untreated patients for the group with high serum alanine aminotransferase (ALT) and with piecemeal necrosis on liver biopsy on entry. The corresponding value was 25% (2 of 8 cases) in treated and 12.5% (1 of 8 cases) in untreated patients with low liver disease activity. Overall, a complete response was thus observed in 23.5% of treated patients and in 12.5% of controls. None of the patients on therapy became HBsAg negative. It is concluded that treatment of heterosexual patients with chronic hepatitis B with r-IFN in the dose regimen used here was not associated with a significant higher rate of serologic and clinical response compared to controls, independently of pretreatment biochemical and histologic activity of liver disease.

Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.

The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e antigen and hepatitis B virus DNA in the serum and hepatitis B core antigen in the liver. Over a 2-year period, no patient experienced a sustained spontaneous remission of disease, and follow-up liver histology revealed worsening of the disease in four patients. After 2 years of observation, 24 patients were allocated randomly to one of two groups: 12 patients served as untreated controls and 12 received recombinant human alpha-interferon-2a in a dose of 9 million units intramuscularly three times weekly for 16 weeks. Patients who remained viremic after 16 weeks received 3 million units three times weekly for an additional 8 weeks. Abnormal amino-transferases and serum hepatitis B virus DNA persisted without appreciable changes in all untreated patients. Hepatitis B virus DNA rapidly became undetectable and serum aminotransferases fell to normal in eight treated patients. After the end of treatment, hepatitis B virus DNA became detectable once again in seven patients, in six of whom a peak of aminotransferases (range: 256 to 850 units per liter) ensued; subsequently, hepatitis B virus DNA disappeared, and serum aminotransferases again fell to normal in two of the seven. Overall, hepatitis B virus DNA was no longer detectable in serum and liver histology improved in three treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)